Genes involved in the <scp>WNT</scp> and vesicular trafficking pathways are associated with melanoma predisposition

Ibarrola‐Villava, Maider; Kumar, Rajiv; Nagore, Eduardo; Benfodda, M.; Guedj, Mickaël; Gazal, Steven; Hu, Hui-Han; Guan, Jian; Rachkonda, P. Sivaramakishna; Descamps, V.; Basset-Séguin, Nicole; Bensussan, Armand; Bagot, M.; Saïag, Philippe; Schadendorf, Dirk; Martín-González, Manuel; Mayor, Matías; Grandchamp, Bernard; Ribas, Gloría; Soufir, Nadem

doi:10.1002/ijc.29257

Cited by 30 publications

(23 citation statements)

References 41 publications

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“…The proliferative stages of melanoma are associated with a peak in canonical Wnt signaling and also increased MITF activity (37). Vesicular trafficking misregulation is emerging as a fundamental hallmark of melanomas and perhaps of other cancers (32,38). Our model helps explain how a lineage-addiction oncogene could cause perturbations in the endolysosomal pathway and increase cellular responses to Wnt signaling (Fig.…”

Section: Discussionmentioning

confidence: 97%

MITF drives endolysosomal biogenesis and potentiates Wnt signaling in melanoma cells

Ploper

Taelman

Robert³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

205

217

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Canonical Wnt signaling plays an important role in development and disease, regulating transcription of target genes and stabilizing many proteins phosphorylated by glycogen synthase kinase 3 (GSK3). We observed that the MiT family of transcription factors, which includes the melanoma oncogene MITF (micropthalmiaassociated transcription factor) and the lysosomal master regulator TFEB, had the highest phylogenetic conservation of three consecutive putative GSK3 phosphorylation sites in animal proteomes. This finding prompted us to examine the relationship between MITF, endolysosomal biogenesis, and Wnt signaling. Here we report that MITF expression levels correlated with the expression of a large subset of lysosomal genes in melanoma cell lines. MITF expression in the tetracycline-inducible C32 melanoma model caused a marked increase in vesicular structures, and increased expression of late endosomal proteins, such as Rab7, LAMP1, and CD63. These late endosomes were not functional lysosomes as they were less active in proteolysis, yet were able to concentrate Axin1, phospho-LRP6, phospho-β-catenin, and GSK3 in the presence of Wnt ligands. This relocalization significantly enhanced Wnt signaling by increasing the number of multivesicular bodies into which the Wnt signalosome/ destruction complex becomes localized upon Wnt signaling. We also show that the MITF protein was stabilized by Wnt signaling, through the novel C-terminal GSK3 phosphorylations identified here. MITF stabilization caused an increase in multivesicular body biosynthesis, which in turn increased Wnt signaling, generating a positive-feedback loop that may function during the proliferative stages of melanoma. The results underscore the importance of misregulated endolysosomal biogenesis in Wnt signaling and cancer.MITF | Wnt-STOP | lysosome | melanoma | multivesicular body

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Section: Discussionmentioning

confidence: 97%

MITF drives endolysosomal biogenesis and potentiates Wnt signaling in melanoma cells

Ploper

Taelman

Robert³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

205

217

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“…Indeed, several genes responsible for inheritable melanoma predisposition have been identified; however, our knowledge on this field is still limited. 20 In particular, correlation between the circadian status and melanoma occurrence may be explored in further details. Skin cells indeed, possess an intrinsic and complex circadian clock organization.…”

Section: Introductionmentioning

confidence: 99%

A polymorphic GGC repeat in the NPAS2 gene and its association with melanoma

Franzoni

Markova-Car

Pavlić

et al. 2017

Exp Biol Med (Maywood)

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This report describes a variable microsatellite repeat sequence located in the 5 0 untranslated exon of NSPAS2, a gene encoding a clock transcription factor. Significantly, this study is the first to show that a variant copy number GGC repeat sequence in the NPAS2 clock gene associates with melanoma risk and which may be useful in the assessment of melanoma predisposition. AbstractCircadian clock regulation in mammals is controlled by feedback loops of a set of circadian genes. One of these circadian genes, NPAS2, encodes for a member of the bHLH-PAS class of transcription factors and is expressed in the forebrain and in some peripheral organs such as liver and skin. Other biological processes are also regulated by circadian genes. For example, NPAS2 is involved in cell proliferation, DNA damage repair and malignant transformation. Aberrant expression of clock genes has been previously observed in melanoma which led to our effort to sequence the NPAS2 promoter region in this cancer type. The NPAS2 putative promoter and 5 0 untranslated region of ninety-three melanoma patients and ninety-six control subjects were sequenced and several variants were identified. Among these is a novel microsatellite comprising a GGC repeat with different alleles ranging from 7 to 13 repeats located in the 5 0 untranslated exon. Homozygosity of an allele with nine repeats (9/9) was more prevalent in melanoma than in control subjects (22.6% and 13.5%, respectively, P: 0.0206) suggesting that some NPAS2 variants might contribute to melanoma susceptibility.

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“…Polymorphisms showing potential differences in allelic effect by sex are located on genes that have functions related to melanocyte development, melanosome formation, maturation and transportation, as well as to skin cancer (26)(27)(28)31,54,56,158,(168)(169)(170).…”

Section: Association With Phenotypic Characteristics By Sexmentioning

confidence: 99%

“…We selected genes previously associated with pigmentation pathways and/or melanoma risk (28,157,168,197,198), preferably including direct targets of functional miRNA that happen to be deregulated in melanoma. Ensembl BioMart (http://www.ensembl.org/biomart/martview) was used to retrieve germline variants from all genes selected.…”

Section: Snp Selectionmentioning

confidence: 99%

“…Melanoma incidence reveals a clear relationship between pigmentation traits and sunlight damage, with individuals with fair skin, green and blue eyes, red and blond hair, high naevus count, freckles, and inability to tan showing greater melanoma susceptibility (9). These phenotypic traits has been shown to be genetically determined by genes implicated in pigmentation and tanning ability (23,31), and genetic variations in these genes have been associated with the susceptibility to melanoma (26,28,29,54,68,157,168). Factors that are mainly involved in the aetiology of melanoma are not only of pigmentary/genetic nature, but also of environmental nature (186).…”

Section: Introductionmentioning

confidence: 99%

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The genetic basis of sunlight sensitivity and melanoma-risk pigmentation phenotypes: The role of sex-specific genetic effects, 3' untranslated regions and melanoma susceptibility genes

Fuster¹

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AGRADECIMIENTOSAntes de presentar este trabajo, es momento de agradecer el respaldo de todas aquellas personas que han hecho posible que hoy sea una finisher de esta carrera de larga distancia que es hacer una tesis doctoral.Mis primeras líneas de agradecimiento son para mi director, Conrado Martínez-Cadenas, y co-directora de tesis, Gloria Ribas; quienes con su dedicación, experiencia y profesionalidad me han guiado de manera excepcional durante las diferentes fases de este trabajo, tanto en el proceso puramente experimental como en el análisis, interpretación y presentación de los datos. A Conrado, gracias por darme la oportunidad de realizar la tesis en su grupo de investigación, además de por su apoyo personal, confianza, cercanía y dedicación. Gracias por mover cielo y tierra porque esto fuera posible. A Gloria, gracias por abrirme las puertas de su laboratorio y, sobre todo, por sus excepcionales consejos que, no sólo me han ayudado a desarrollar esta tesis, sino que también han permitido la publicación de los resultados obtenidos.Gracias a Maider Ibarrola-Villava y Maria Peña-Chilet, miembros del grupo de investigación del Departamento de Oncología del INCLIVA, por acompañarme en este largo camino, por su valiosa aportación y su gran compañerismo.Gracias a Zalfa Abdel-Malek por acogerme en su laboratorio y darme la oportunidad de participar en un ambicioso proyecto que ha enriquecido sustancialmente mi carrera investigadora. Gracias por su exigencia y crítica constructiva, pero también por su cariño durante mi estancia. Mención especial a Vicky Sope y Renny Starner por su incalculable ayuda, paciencia y amistad. Gracias de corazón por dejarme empapar de vuestra profesionalidad.Gracias a todo el personal de la Unidad Predepartamental de Medicina de la Universitat Jaume I de Castellón, por el buen humor y compañerismo demostrado. Mención especial para mis compañeros de batalla en el laboratorio. Gracias por esas largas conversaciones y hacerme sentir afortunada por compartir mi trabajo diario con vosotros. Gracias por todo lo compartido.Gracias también a todas esas personas anónimas que voluntariamente han donado una muestra, y al personal médico de los diferentes hospitales encargados de recoger dichas muestras, ya que sin su contribución este trabajo no habría existido.Finalmente, es necesario expresar mi mayor gratitud a todas esas personas que indirectamente también han sido partícipes de este trabajo. A mi familia, por creer en mí.A mi padre, por enseñarme el valor del esfuerzo, el trabajo duro y la disciplina. A mi madre, por enseñarme a tener paciencia. A mi hermana, por ser mi mejor amiga y consejera, especialmente en la estadística y el uso del R. A Manoli, porque todo lo vivido juntas es lo que me ha hecho ser lo que soy. A mi grupo de entrenamiento, por ayudarme a evadirme de todo en los momentos que más lo necesitaba. A Iván, por estar siempre a mi lado. Por no dejarme caer. Por saber cómo hacer que confiara en mi misma. Por hacerme ver que soy una privilegiada hasta en los momentos menos buenos...

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Genes involved in the WNT and vesicular trafficking pathways are associated with melanoma predisposition

Cited by 30 publications

References 41 publications

MITF drives endolysosomal biogenesis and potentiates Wnt signaling in melanoma cells

MITF drives endolysosomal biogenesis and potentiates Wnt signaling in melanoma cells

A polymorphic GGC repeat in the NPAS2 gene and its association with melanoma

The genetic basis of sunlight sensitivity and melanoma-risk pigmentation phenotypes: The role of sex-specific genetic effects, 3' untranslated regions and melanoma susceptibility genes

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